Green fluorescent protein (GFP)-based calcium probes have been developed, but their limited signal intensity has made it difficult to measure calcium concentrations with good spatial and temporal resolution. On page 137 Nakai et al. describe a high-affinity calcium probe based upon a previously described circularly permutated enhanced GFP (cpEGFP) molecule. They engineered the probe by attaching the N terminus of the cpEGFP molecule to the M13 fragment of myosin light chain kinase—the target sequence of the calcium-binding protein calmodulin—and they then connected the C terminus to calmodulin. When calcium binds to calmodulin, conformational changes due to the calcium–calmodulin–M13 interaction induce a subsequent conformational change in cpEGFP, so that the fluorescence intensity changes. The authors observed large fluorescence changes in cells expressing the sensor in response to application of drugs or electrical stimulation. The sensor will be a useful tool for visualizing calcium in living cells.